The treatment of posttraumatic stress disorder (PTSD) has been mostly focused on the alleviation of the symptoms by counseling such as exposure therapy and cognitive restructuring. Although medication therapy is available, only indirect palliatives such as antidepressants are used, which makes it hard to treat critical PTSD patients.
Meanwhile, although there are various methods for treating patients suffering from drug addiction or phobia, repeated memory renewal after the treatment is the most prominent clinical difficulty. Therefore, there exists a need to investigate physiological mechanism of memory renewal for preventing renewal of drug addiction/fear memory.
The α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is an ionotropic glutamate receptor that mediates fast synaptic transmission in the central nervous system (CNS). AMPARs are composed of four types of subunits, designated GluR1, GluR2, GluR3, and GluR4. Ca2+ permeability of AMPAR depends on the constitution of the subunits, i.e., receptors having GluR2 subunit show low Ca2+ permeability while receptors having no GluR2 subunit show high Ca2+ permeability (Trends Neurosci. 16, 359-365, 1993; Annu. Rev. Neurosci. 17, 31-108, 1994; Prog. Neurobiol. 54, 581-618, 1998).
GluR2-lacking AMPAR antagonists, mostly derivatives of spermine, have been reported to be useful for treating epilepsy and cerebral infarction (Yoneda et. al., Bioorg Med Chem. 11(10), 1261-1264, 2001). However, it has not been reported whether GluR2-lacking AMPAR antagonists may be effective in the treatment of PTSD, drug addiction or phobia.